PRO-SOMATOSTATIN-RELATED PEPTIDES

生长抑素原相关肽

基本信息

批准号：
2139300
负责人：
JOHN W ENSINCK
金额：
$ 24.88万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-09-01 至 1997-03-31
项目状态：
已结题

项目摘要

Our overall hypothesis is that insulinotropic peptides from the GI tract ("incretins") and somatostatin-28 (S-28), a "decretin", modulate insulin secretion in a coordinate manner during absorption and assimilation of nutrients. We also postulate that substrate-induced release of the "incretin" glucagon-like peptide-1 7-36 amide [tGLP-1] from enterocytes is not a direct process but rather is indirectly mediated through neurotransmitters secreted from intestinal cells responding specifically to luminal nutrients. A derivative hypothesis is that tGLP-1 also has an ancillary function to enhance glucose disposition during nutrient absorption. specific questions include: 1) Do intestinal endocrine epithelial cells (enterocytes) that secrete GIP, tGLP-1 and S-28 respond directly to specific substrates? 2) Do "incretins" and S-28 modulate the kinetics of insulin secretion during nutrient absorption? 3) Does tGLP-1 modulate postprandial glucose disposition independent of its insulinotropic action? a) if so, does it affect peripheral glucose utilization and/or hepatic glucose production (HGO), and b) are these putative actions dependent on insulin and/or the release of glucagon. These hypotheses and questions are derived from evidence in vitro and in vivo that GIP and tGLP-1 potentiate glucose-mediated insulin secretion whereas S-28 inhibits it. In vitro data suggests that this may result from a shift in threshold and rate of insulin release and that there may be subpopulations of B-cells which respond at different thresholds. Furthermore, indirect evidence suggests that the release of the enteric peptides during nutrient intake may not be due to a direct effect of the substrates on their release from specific enterocytes. To address these questions we will evaluate the effects of tGLP-1 and S-28 separately and together on the threshold of rate of insulin secretion in isolated islets and in humans. The physiologic role of S-28 as a putative modulator of insulin secretion in vivo will be indirectly evaluated in humans using omeprazole and loxiglumide, recently discovered inhibitors of S-28 secretion. to determine if nutrients directly elicit enteropeptide secretion or do so via receptors on neural cells which then signal enterocytes, we will test the effects of specific nutrient constituents and neurotransmitters in cultured monkey enterocytes. Recently published data implies an additional, unexpected action of tGLP-1 in either potentiating or mimicking the action of insulin on glucose disposition in humans. We will examine this issue in humans by measuring glucose disposal and HGO isotopically, at clamped insulin and glucagon levels, during tGLP-1 infusions. The results of the experiments should provide a more comprehensive view of the physiologic importance of the "enteroinsular axis" in fuel homeostasis.

我们的总体假设是来自胃肠道的促胰岛素肽（“肠促胰岛素”）和生长抑素-28 (S-28)，一种“促胰岛素”，调节胰岛素在吸收和同化过程中协调分泌营养素。我们还假设底物诱导的释放来自肠细胞的“肠促胰岛素”胰高血糖素样肽-1 7-36 酰胺 [tGLP-1] 不是一个直接的过程，而是通过以下方式间接介导的：由肠道细胞分泌的神经递质特异性反应到腔内营养物质。衍生假设是 tGLP-1 也具有营养期间增强葡萄糖处置的辅助功能吸收。具体问题包括： 1）做肠道内分泌分泌 GIP、tGLP-1 和 S-28 的上皮细胞（肠上皮细胞）做出反应直接作用于特定基材？ 2) “肠促胰素”和 S-28 是否调节营养吸收过程中胰岛素分泌的动力学？ 3) tGLP-1 是否有效调节餐后血糖分布，与其无关促胰岛素作用？ a) 如果是这样，是否会影响外周血糖利用和/或肝葡萄糖产生（HGO），b）是这些假定的作用依赖于胰岛素和/或胰高血糖素的释放。这些假设和问题源自体外和体内的证据体内 GIP 和 tGLP-1 增强葡萄糖介导的胰岛素分泌而S-28则抑制它。体外数据表明这可能会导致来自胰岛素释放阈值和速率的变化，并且可能有是在不同阈值下做出反应的 B 细胞亚群。此外，间接证据表明肠溶的释放营养素摄入过程中的肽可能不是由于底物从特定肠细胞释放。为了解决这些我们将分别评估 tGLP-1 和 S-28 的效果，共同研究孤立胰岛胰岛素分泌率的阈值和人类。 S-28 作为假定的调节剂的生理作用将使用以下方法间接评估人体体内的胰岛素分泌奥美拉唑和洛昔格鲁胺，最近发现的 S-28 抑制剂分泌。确定营养素是否直接引发肠肽分泌或通过神经细胞上的受体进行，然后发出信号肠细胞，我们将测试特定营养成分的影响和培养猴肠细胞中的神经递质。最近发表数据暗示 tGLP-1 在以下任一方面有额外的、意想不到的作用：增强或模拟胰岛素对葡萄糖处置的作用在人类中。我们将通过测量葡萄糖来研究人类的这个问题在固定的胰岛素和胰高血糖素水平下进行处置和 HGO 同位素，在 tGLP-1 输注期间。实验结果应提供对生理重要性有更全面的认识燃料稳态中的“肠岛轴”。